Method and composition for rejuvenating hair, nails, tissues, cells and organs by ex-vivo or immersive treatment

ABSTRACT

A method and composition for the treatment of hair, nail, ex-vivo organ, ex-vivo cell or ex-vivo tissue to improve the biomechanical and diffusional characteristics comprising an effective amount of a compound selected from the group consisting of compounds of the formula (I):  
                 
 
     or the formula (II):

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. 119(e) ofU.S. Provisional Application Serial No. 60/263,300, filed Jan. 22, 2001.

BACKGROUND OF THE INVENTION

[0002] The present invention generally relates to the aging or damage ofhair, nails, tissues, organs and cells and, more particularly, to therejuvenation of hair, nails, tissues, cells, and organs by improving thedeformability and diffusion coefficient of hair, nails, tissues, cells,and organs in humans and animals (including companion animals and livestock).

[0003] Various changes in the biomechanical and other functionalproperties of hair may occur with aging and diseases. Undesirablechanges may include deterioration in manageability, including decreasedstability and brittle hair. Typically, these detrimental changes may bedue to: (a) physically or chemically damaged hair; (b) physiologicallyaged hair; and/or (c) diseased hair (e.g. hair of diabetics). Hair maybe physically damaged from the normal grooming process of shampooing,combing, drying (e.g. hot air blow drying), and/or brushing. In additionto this physical damage of hair, hair may also be damaged by chemicalaction such as by exposure to sunlight and contact with water containingchemically reactive agents such as oxidizers (e.g bleaching and/ordyeing of hair). Also, the repeated use of permanent waving compositionson the hair fibers may cause damage to the hair especially if not usedaccording to directions. Bleached hair is often characterized as beingdry, brittle, and overly coarse. Finally, with the aging process, hairmay become dry, brittle and overly coarse.

[0004] For nails, deterioration in the biomechanical and otherfunctional properties may also result in undesirable nail problems.Conventionally, the term “nail” has meant the horny cutaneous plate onthe dorsal surface of the distal end of a finger or toe, or thecorresponding appendages in animals. Specifically, in humans, thehardness and strength of the nails is particularly important not onlyfor the beauty of their appearance, but for the well-being of theindividual. Embrittlement of the nails is normally associated withaging. However, various activities also expose nails to a number ofmaterials which may adversely affect the nail's biomechanical and otherfunctional properties. For example, occupational exposure to extensiveor constant wetting of the hands with soaps, detergents, solvents,chemical hair waving and coloring lotions, and insults from deliberatecosmetic applications, such as manicuring, or any like products can leadto drying, brittleness, cracking, laminating, splitting, ridging andsimilar damage. Additionally, certain diseases may also lead to nailembrittlement or associated disfigurement owing to weakening of nailhardness and strength. Moreover, the appearance of fingernails andtoenails of humans are frequently enhanced with decorative nail-carecosmetics, such as nail polishes, nail polish removers, nail polishbases, alkaline cuticle removers and the like. Overuse of these productscan alter the nail, causing it to weaken, soften, split and break.

[0005] With respect to tissues, cells and organs, transplantation ofthese materials has become a routine means of treating certain diseasesand other conditions. Transplantation requires a ready source of organs,such as kidney, pancreas, liver, heart, etc., from living persons orcadavers. Conventionally, most vital organs, cells and tissues, whichare used for transplantation, are obtained from heart beating cadaversand preserved for variable periods of time prior to theirtransplantation. However, preservation methods merely attempt tomaintain the present condition of the organ, cell or tissue. For thisreason, the majority of organs, cells and tissues that are used fortransplantation presently come from younger individuals who typicallyhave tissues, cells and organs that have not been detrimentally affectedby age or disease.

[0006] In contrast, because of the aging process or disease, olderindividuals have a deterioration in the biomechanical (e.g.deformability) and other functional properties of their cells, tissuesand organs. For this reason, decreased deformability is associated withimpaired tissue or organ functionality in itself, as optimalbiomechanical function is demonstrated at deformability levels measuredin young individuals and diminishes with progressively decreasing levelsof deformability. Thus, at the present time, older individuals typicallycan not be candidates for organ, tissue or cell donation becausepreservation solutions merely attempt to preserve the present conditionof the organ, cell or tissue.

[0007] Conventionally, two typical methods of preserving organs, cellsand tissues for transplantation are continuous pulsatile perfusion andsimple hypothermic storage in a preservation solution. In pulsatileperfusion, the organ is subjected to pulsatile flow of a perfusate underhypothermic conditions such that the organ membranes receive sufficientoxygenation. Typically, the perfusate contains albumin and lipids. Withsimple hypothermic storage, organs are removed from a cadaver donor andrapidly cooled. Rapid cooling is achieved by external cooling and byperfusion with a preservation solution to lower the internal temperatureof the organ. The organ is then stored immersed in the preservationsolution at temperatures of about 0°-4° C. Two conventional glucosepreservation flush solutions are the Collins (G. M. Collins, The Lancet,1969, 1219-1222) and the Euro-Collins (J. P. Squifflet et al,Transplant. Proc., 1981, 13:693-696) solutions. These solutions resembleintracellular fluid and contain glucose as an osmotic agent. Despitetheir widespread use, the Collins and Euro-Collins preservationsolutions do not typically provide adequate preservation for storagetimes greater than about 48 hours. For example, kidneys stored inCollins solution for 24 hours may exhibit considerable damage to thenephrons. This damage included degradation of cells lining the proximaltubules, extensive swelling and rupturing of cells lining the ascendingdistal tubules, degeneration of glomerular epithelial and endothelialcells and accumulation of flocculent cytoplasmic debris in the capsularspaces of Bowman. (P. M. Andrews et al, Lab. Invest., 1982, 46:100-120).In addition to glucose flush solutions, high osmolality preservationsolutions have been prepared using raffinose and lactobionate as in theUW preservation solution (R. J. Ploeg et al, Transplant. Proc., 1988, 20(suppl 1) 1:935-938), mannitol in the Sacks solution (S. A. Sacks, TheLancet, 1973, 1:1024-1028), sucrose in the phosphate buffered sucrose(PBS) preservation solution (F. T. Lam et al, Transplantation, 1989,47:767-771) and the histidine buffered HTK solution of Bretschneider (N.M. Kallerhoff et al, Transplantation, 1985, 39:485-489). Other examplesare solutions that contain synthetic hydroxyethyl starch (HES) as anosmotic colloid.

SUMMARY OF THE INVENTION

[0008] In accordance with the present invention, a novel method andcomposition are disclosed for the “rejuvenation” of hair, nails,tissues, cells and organs by ex-vivo treatment. In particular, thecomposition comprises compounds for the ex-vivo treatment of hair,nails, tissues, cells and organs to improve the biomechanical and otherfunctional properties of hair, nails, tissues, cells and organs. Moreparticularly, for hair and nails, the composition and method of thepresent invention comprises compounds for rejuvenating: (a) damaged hairor nails; (b) physiologically aged hair or nails; and/or (c) diseasedhair or nails (e.g. diabetes). For tissues, cells and organs, thecomposition and method of the present invention comprises compounds forrejuvenating tissues, cells and organs by improving the deformabilityand/or diffusion coefficient of tissues, cells and organs from a stateof decreased deformability and impaired diffusional characteristics, astypically observed in cells, tissues or organs of older individuals, toa state of increased deformability and improved diffusionalcharacteristics, as commonly seen in cells, tissues and organs ofhealthy and young individuals (i.e 20 years old).

[0009] Decreased deformability is associated with impaired tissue ororgan functionality in itself, as optimal biomechanical function isdemonstrated at deformability levels measured in young individuals anddiminishes progressively with age. It is believed that the agingprocess, in addition to modifying the deformability, also inducesadditional specific impairments in the functionality of cells, tissuesand/or organs that are not directly related to deformability. It isfurther believed that this impairment in functionality is related to analtered diffusion coefficient of molecules across intracellular andextracellular spaces. The altered ability of molecules to traverseintra- and extracellular spaces may affect signaling functions ofhormones and cytokines, transportation of oxygen and nutrients from thevascular space to the cell, and cellular metabolism.

[0010] Commonly used methods to determine deformability includeultrasonographic techniques and the measurement of volume-pressure andstress-strain relationships. Commonly used methods to measure thediffusion coefficient of molecules across intracellular andextracellular spaces include the determination of the reaction time ofbiomolecular feed-back mechanisms based on the diffusion of moleculesacross a cellular, tissue and/or organ space to reach a target responseelement and the direct measurement of the diffusion rate of certainmolecules across biological spaces. Examples of methods to determine thebiomolecular feed-back mechanisms include, but are not limited to, thefollowing: (a) hypothalamic-pituitary axis: growth hormone, ACTH, TSH,or prolactin; (b) pituitary-adrenal axis: cortisol; (c)pituitary-thyroid axis: thyroxin; and (d) pituitary-gonadal axis: sexhormones, LH, and FSH. Examples of methods to determine the diffusionrate of certain molecules across biological spaces include, but are notlimited to, the following: arterio-alveolar oxygen and carbon dioxidegradients; insulin resistance; and arterio-venous oxygen gradient (e.g.,heart, muscle).

[0011] In particular, the compositions comprise compounds for theex-vivo treatment of hair, nails, organs, cells and tissues torejuvenate them by changing deformability and increase the tissuediffusion coefficient. This treatment is accomplished by bathing orperfusing the biological material outside of the body. The compounds aremembers of the class of compounds known as thiazoliums.

[0012] In one embodiment, the compositions comprise thiazolium compoundshaving the following structural formula (I):

[0013] wherein R¹ and R² are independently selected from the groupconsisting of hydrogen, hydroxy(lower alkyl), lower acyloxy(loweralkyl), lower alkyl, lower alkenyl, or R¹ and R² together with theirring carbons may be an aromatic fused, ring, optionally substituted byone or more amino, halo or alkylenedioxy groups;

[0014] Z is hydrogen or an amino group;

[0015] Y is amino, a group of the formula —CH₂C(═O)—R wherein R is alower alkyl, alkoxy, hydroxy, amino or aryl group; said aryl groupoptionally substituted by one or more lower alkyl, lower alkoxy, halo,dialkylamino, hydroxy, nitro or alkylenedioxy groups;

[0016] or a group of the formula —CH₂R′ wherein R′ is hydrogen, or alower alkyl, lower alkynyl, or aryl group;

[0017] or a group of the formula —CH₂C(═O)—N(R″)R′″ wherein (a) R″ ishydrogen and R′″ is a lower alkyl group, optionally substituted by aC₆-C₁₀ aryl group, or a C₆-C₁₀ aryl group, said aryl groups optionallysubstituted by one or more lower alkyl, halo, or (lower alkoxyl)carbonylgroups; or (b) R″ and R′″ are both lower alkyl groups;

[0018] X is a halide, tosylate, methanesulfonate, mesitylenesulfonateion, or other pharmaceutically acceptable anion and mixtures thereof,and a carrier therefor.

[0019] In another embodiment, the composition comprises compounds havingthe following structural formula (II):

[0020] wherein R¹ and R² are independently selected from the groupconsisting of hydrogen and an alkyl group optionally substituted by ahydroxy group;

[0021] Y is a group of the formula —CH₂C(═O)R wherein R is aheterocyclic group other than alkylenedioxyaryl containing 4-10 ringmembers and 1-3 heteroatoms selected from the group consisting ofoxygen, nitrogen and sulfur; said heterocyclic group optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl groups;and said one or more substituents optionally substituted by one or morealkyl or alkoxy groups;

[0022] or a group of the formula —CH₂C(═O)—NHR′ wherein R′ is aheterocyclic group containing 4-10 ring members and 1-3 heteroatomsselected from the group consisting of oxygen, nitrogen, and sulfur; saidheterocyclic group optionally substituted by one or morealkoxycarbonylalkyl groups;

[0023] and X is a halide, tosylate, methanesulfonate ormesitylenesulfonate ion, or other pharmaceutically acceptable anion.

[0024] The present invention also relates to a method for treating hairand nails and for the ex-vivo rejuvenation of organs, cells and tissuesby contacting the hair and/or nails or ex-vivo organs, cells or tissueswith a sufficient amount of one or more of the compounds of the presentinvention, or a composition containing a sufficient amount to achievethe desired result.

DETAILED DESCRIPTION OF THE INVENTION

[0025] A method and composition are disclosed for the “rejuvenation” ofhair, nails, tissues, cells and organs by ex-vivo treatment. Inparticular, the composition comprises compounds for ex-vivo treatinghair, nails, tissues, cells and organs to improve the biomechanical andother functional properties of hair, nails, tissues, cells and organs.More particularly, for hair and nails, the composition and method of thepresent invention comprises compounds for rejuvenating: (a) damaged hairor nails; (b) physiologically aged hair or nails; and/or (c) diseasedhair or nails (e.g. diabetes). For tissues, cells and organs, thecomposition and method of the present invention comprise compounds forrejuvenating tissues, cells and organs by improving the deformabilityand/or diffusion coefficient of tissues, cells and organs from a stateof decreased deformability and impaired diffusional characteristics, astypically observed in cells, tissues or organs of older individuals, toa state of increased deformability and improved diffusionalcharacteristics, as commonly seen in cells, tissues and organs ofhealthy and young individuals (i.e 20 years old).

[0026] In one embodiment, the invention relates to a composition for theex-vivo treatment of hair, nails, organs, cells and tissues to improvethe biomechanical and functional properties comprising one or moreagents comprising of thiazole compounds having the structural formula(I):

[0027] wherein R¹ and R² are independently selected from the groupconsisting of hydrogen, hydroxy(lower alkyl), lower acyloxy(loweralkyl), lower alkyl, lower alkenyl, or R¹ and R² together with theirring carbons may be an aromatic fused, ring, optionally substituted byone or more amino, halo or alkylenedioxy groups;

[0028] Z is hydrogen or an amino group;

[0029] Y is amino, a group of the formula —CH₂C(═O)R wherein R is alower alkyl, alkoxy, hydroxy, amino or aryl group; said aryl groupoptionally substituted by one or more lower alkyl, lower alkoxy, halo,dialkylamino, hydroxy, nitro or alkylenedioxy groups;

[0030] or a group of the formula —CH₂ R′ wherein R′ is hydrogen, or alower alkyl, lower alkynyl, or aryl group;

[0031] or a group of the formula —CH₂C(═O)—N(R″)R′″ wherein (a) R″ ishydrogen and R′″ is a lower alkyl group, optionally substituted by aC₆-C₁₀ aryl group, or a C₆-C₁₀ aryl group, said aryl groups optionallysubstituted by one or more lower alkyl, halo, or (lower alkoxy)carbonylgroups; or (b) R′ and R′″ are both lower alkyl groups;

[0032] X is a halide, tosylate, methanesulfonate, mesitylenesulfonate,or other pharmacologically acceptable anion and mixtures thereof, and acarrier therefor.

[0033] The lower alkyl groups referred to above contain 1-6 carbon atomsand include methyl, ethyl, propyl, butyl, pentyl, hexyl, and thecorresponding branched-chain isomers thereof. The lower alkenyl groupsand lower alkynyl groups independently contain from 2 to 6 carbon atoms.Similarly, the lower alkoxy groups contain from 1 to 6 carbon atoms, andinclude methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy, and thecorresponding branched-chain isomers thereof. These groups areoptionally substituted by one or more halo, hydroxy, amino or loweralkylamino groups.

[0034] The lower acyloxy(lower alkyl) groups encompassed by the aboveformula include those wherein the acyloxy portion contains from 2 to 6carbon atoms and the lower alkyl portion contains from 1 to 6 carbonatoms. Typical acyloxy portions are those such as acetoxy orethanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, andthe corresponding branched chain isomers thereof. Typical lower alkylportions are as described hereinabove. The aryl groups encompassed bythe above formula are those containing 6-10 carbon atoms, such as phenyland lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and areoptionally substituted by 1-2 halo, hydroxy, lower alkoxy or di(loweralkyl)amino groups. Preferred aryl groups are phenyl, methoxyphenyl and4-bromophenyl groups. The halo atoms in the above formula may be fluoro,chloro, bromo or iodo.

[0035] For the purposes of this invention, the compounds of formula (I)are formed as biologically and pharmaceutically acceptable salts. Usefulsalt forms are the halides, particularly the bromide and chloride,tosylate, methanesulfonate, and mesitylenesulfonate salts. Other relatedsalts can be formed using similarly non-toxic, and biologically andpharmaceutically acceptable anions.

[0036] Representative compounds of the present invention are:

[0037] 3-aminothiazolium mesitylenesulfonate;

[0038] 3-amino-4,5-dimethylaminothiazolium mesitylenesulfonate;

[0039] 2,3-diaminothiazolium mesitylenesulfonate;

[0040] 3-(2-methoxy-2-oxoethyl)thiazolium bromide;

[0041] 3-(2-methoxy-2-oxoethyl)-4,5-dimethylthiazolium bromide;

[0042] 3-(2-methoxy-2-oxoethyl)-4-methylthiazolium bromide;

[0043] 3-(2-phenyl-2-oxoethyl)-4-methylthiazolium bromide;

[0044] 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide;

[0045] 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride;

[0046] 3-amino-4-methylthiazolium mesitylenesulfonate;

[0047] 3-(2-methoxy-2-oxoethyl)-5-methylthiazolium bromide;

[0048] 3-(3-(2-phenyl-2-oxoethyl)-5-methylthiazolium bromide;

[0049] 3-[2-(4-bromophenyl)-2-oxoethyl]thiazolium bromide;

[0050] 3-[2-(4-bromophenyl)-2-oxoethyl]-4-methylthiazolium bromide;

[0051] 3-[2-(4-bromophenyl)-2-oxoethyl]-5-methylthiazolium bromide;

[0052] 3-[2-(4-bromophenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;

[0053] 3-(2-methoxy-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide;

[0054] 3-(2-phenyl-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide;

[0055]3-[2-(4-bromophenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide;

[0056] 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide;

[0057] 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide;

[0058] 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride;

[0059] 3-(2-methoxy-2-oxoethyl)benzothiazolium bromide;

[0060] 3-(2-phenyl-2-oxoethyl)benzothiazolium bromide;

[0061] 3-[2-(4′-bromophenyl)-2-oxoethyl]benzothiazolium bromide;

[0062] 3-(carboxymethyl)benzothiazolium bromide;

[0063] 2,3-diaminobenzothiazolium mesitylenesulfonate;

[0064] 3-(2-amino-2-oxoethyl)thiazolium bromide;

[0065] 3-(2-amino-2-oxoethyl)-4-methylthiazolium bromide;

[0066] 3-(2-amino-2-oxoethyl)-5-methylthiazolium bromide;

[0067] 3-(2-amino-2-oxoethyl)4,5-dimethylthiazolium bromide;

[0068] 3-(2-amino-2-oxoethyl)benzothiazolium bromide;

[0069] 3-(2-amino-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide;

[0070] 3-amino-5-(2-hydroxyethyl)-4-methylthiazoliummesitylenesulfonate;

[0071] 3-(2-methyl-2-oxoethyl)thiazolium chloride;

[0072] 3-amino-4-methyl-5-(2-acetoxyethyl)thiazoliummesitylenesulfonate;

[0073] 3-(2-phenyl-2-oxoethyl)thiazolium bromide;

[0074] 3-(2-methoxy-2-oxoethyl)-4-methyl-5-(2-acetoxyethyl)thiazoliumbromide;

[0075] 3-(2-amino-2-oxoethyl)-4-methyl-5-(2-acetoxyethyl)thiazoliumbromide;

[0076] 2-amino-3-(2-methoxy-2-oxoethyl)thiazolium bromide;

[0077] 2-amino-3-(2-methoxy-2-oxoethyl)benzothiazolium bromide;

[0078] 2-amino-3-(2-amino-2-oxoethyl)thiazolium bromide;

[0079] 2-amino-3-(2-amino-2-oxoethyl)benzothiazolium bromide;

[0080] 3-[2-(4-methoxyphenyl)-2-oxoethyl]thiazolium bromide;

[0081] 3-[2-(2,4-dimethoxyphenyl)-2-oxoethyl]thiazolium bromide;

[0082] 3-[2-(4-fluorophenyl)-2-oxoethyl]thiazolium bromide;

[0083] 3-[2-(2,4-difluorophenyl)-2-oxoethyl]thiazolium bromide;

[0084] 3-[2-(4-diethylaminophenyl)-2-oxoethyl]thiazolium bromide;

[0085] 3-propargylthiazolium bromide;

[0086] 3-propargyl-4-methylthiazolium bromide;

[0087] 3-propargyl-5-methylthiazolium bromide;

[0088] 3-propargyl-4,5-dimethylthiazolium bromide;

[0089] 3-propargyl-4-methyl-5-(2-hydroxyethyl)thiazolium bromide.(2-(3-methoxyphenyl)-2-oxoethyl)thiazolium bromide;

[0090] 3-(2-(3-methoxyphenyl)-2-oxoethyl)-4methyl-5-(2-hydroxyethyl)thiazolium bromide;

[0091] 3-(2-(3-methoxyphenyl)-2-oxoethyl)benzothiazolium bromide;

[0092] 2,3-diamino-4-chlorobenzothiazolium mesitylenesulfonate;

[0093] 2,3-diamino-4-methylthiazolium mesitylenesulfonate;

[0094] 3-amino-4-methyl-5-vinylthiazolium mesitylenesulfonate;

[0095] 2,3-diamino-6-chlorobenzothiazolium mesitylenesulfonate;

[0096] 2,6-diaminobenzothiazole dihydrochloride;

[0097] 2,6-diamino-3-(2-(4-methoxyphenyl)-2-oxoethyl)benzothiazoliumbromide;

[0098] 2,6-diamino-3-(2-(3-methoxyphenyl)-2-oxoethyl)benzothiazoliumbromide;

[0099]2,6-diamino-3-(2-(4-diethylaminophenyl)-2-oxoethyl)benzothiazoliumbromide;

[0100] 2,6-diamino-3-(2-(4-bromophenyl)-2-oxoethyl)benzothiazoliumbromide;

[0101] 2,6-diamino-3-(2-(2-phenyl-2-oxoethyl)benzothiazolium bromide;

[0102] 2,6-diamino-3-(2-(4-fluorophenyl-2-oxoethyl)benzothiazoliumbromide;

[0103] 3-acetamido-4-methyl-5-(2-acetoxyethyl)thiazoliummesitylenesulfonate;

[0104] 2,3-diamino-5-methylthiazolium mesitylenesulfonate;

[0105]3-(2-(2-naphthyl)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide;

[0106] 3 -(2-(3,5- di-tert-butyl-4-hydroxyphenyl)-2 -oxoethyl)-4-methyl-5 -(2-hydroxyethyl)thiazolium bromide;

[0107] 3-(2-(2-(2,6-dichlorophenyl)ethylamino)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide;

[0108]3-(2-dibutylamino-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)-thiazoliumbromide;

[0109] 3-(2-(4-(ethoxycarbonyl)anilino)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide;

[0110] 3-(2-(2,6-diisopropylanilino)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide;

[0111] 3-amino-4-methyl-5-(2-(2,6-dichlorobenzyloxy)ethyl)thioazoliummesitylenesulfonate;

[0112] 3-(2-(4-carbomethoxy-3-hydroxyanilino)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide;

[0113] 2,3-diamino-4,5-dimethylthiazolium mesitylene sulfonate;

[0114] 2,3-diamino-4-methyl-5-(2-hydroxyethyl)thiazolium mesitylenesulfonate;

[0115] 2,3-diamino-5-(3,4-trimethylenedioxy phenyl)thiazolium mesitylenesulfonate;

[0116]3-(2-(1,4-benzodioxan-6-yl)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide;

[0117] 3-(2-(3,4-trimethylenedioxyphenyl)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide;

[0118] 3-(2-(1,4-benzodioxan-6-yl)-2-oxoethyl)thiazolium bromide;

[0119] 3-(2-(3,4-trimethylenedioxyphenyl)-2-oxoethyl)thiazolium bromide;

[0120] 3-(2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl) -thiazoliumbromide;

[0121] 3-(2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl)-4-methylthiazolium bromide;

[0122] 3-(2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl)-5-methylthiazolium bromide;

[0123] 3-(2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide;

[0124]3-(2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl)benzothiazoliumbromide;

[0125] 3-(2-(4-n-pentylphenyl)-2-oxoethyl)thiazolium bromide;

[0126]3-(2-(4-n-pentylphenyl)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide;

[0127] 3-(2-4-diethylaminophenyl)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide;

[0128] 3-(2-phenyl-2-oxoethyl)-4-methyl-5-vinylthiazolium bromide;

[0129] 3-(2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl)-4-methyl-5-vinylthiazolium bromide;

[0130] 3-(2-tert-butyl-2-oxoethyl)thiazolium bromide;

[0131] 3-(2-tert-butyl-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide;

[0132] 3-(3-methoxybenzyl)-4-methyl-5-(2-hydroxyethyl)thiazoliumchloride;

[0133] 3-(2,6-dichlorobenzyl)-4-methyl-5-(2-hydroxyethyl)thiazoliumchloride;

[0134] 3-(2-nitrobenzyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide;

[0135] 3-(2-(4-chlorophenyl)-2-oxoethyl)thiazolium bromide;

[0136]3-(2-(4-chlorophenyl)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide; and

[0137]3-(2-(4-methoxyphenyl)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide.

[0138] U.S. Pat. Nos. 5,656,261 and 6,007,865 disclose the compoundsrepresented by Formula I, and their syntheses, which are herebyincorporated by reference herein.

[0139] In another embodiment, the compositions comprise thiazoliumcompounds having the following structural formula (II):

[0140] wherein R¹ and R² are independently selected from the groupconsisting of hydrogen and an alkyl group optionally substituted by ahydroxy group; Y is a group of the formula —CH₂C(═O)R wherein R is aheterocyclic group containing 4-10 ring members and 1-3 heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur; saidheterocyclic group optionally substituted by one or more substituentsselected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl,aryl, and aralkyl groups; and said one or more substituents optionallysubstituted by one or more alkyl or alkoxy groups;

[0141] or a group of the formula —CH₂C(═O)—NHR′ wherein R′ is aheterocyclic group containing 4-10 ring members and 1-3 heteroatomsselected from the group consisting of oxygen, nitrogen, and sulfur; saidheterocyclic group optionally substituted by one or morealkoxycarbonylalkyl groups;

[0142] and X is a halide, tosylate, methanesulfonate ormesitylenesulfonate ion or other pharmacologically acceptable anion.

[0143] The heterocyclic groups referred to herein include 4-8 memberedrings having at least one and up to 3 heteroatoms, e.g. oxygen nitrogen,or sulfur, therein, and including various degrees of unsaturation.Representatives of such heterocyclic groups are those such asisoxazolyl, phenylisoxazolyl, furanyl, morpholino, thiomorpholino,pyrimidinyl, piperidino, homopiperidino, piperazino, methylpiperazino,hexamethyleneimino, tetrahydroquinolyl, pyridyl, methylpyridyl,imidazolyl, pyrrolidinyl, 2,6-dimethylmorpholino, 1,2,4-triazoylyl,thiazolyl, thienyl, thiazolinyl, methylthiazolyl, and the like. Theheterocyclic groups of the present invention may be further substituted,for example, by an oxo group, to form, for example, a2-oxo-tetrahydroquinolinyl group, or substituted by one or more alkyl,alkoxycarbonylalkyl, aryl, or aralkyl groups, and such substituents maybe further substituted by one or more alkyl or alkoxy groups.

[0144] Examples of Y groups of the compounds of the present inventioninclude, but are not limited to:3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl];3-(2-(4-morpholinyl)-2-oxoethyl);3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl];3-(2-(1-piperidinyl)-2-oxoethyl);3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl];3-(2-(1-pyrrolidinyl)-2-oxoethyl;3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl];3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl; 3-(2-(2-thienyl)-2-oxoethyl);3-(2-(2-thienyl)-2-oxoethyl); 3-(2-(4-thiomorpholinyl)-2-oxoethyl);3-(2-(hexahydro-1-azepinyl)-2-oxoethyl),3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl;3-(2-(octahydro-1-azocinyl)-2-oxoethyl); 3-(2-(2-pyridinyl)-2-oxoethyl;3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl];3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl];3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]; and3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl].

[0145] The alkyl groups referred to above contain one to about eighteencarbon atoms and include, for example, methyl, ethyl, propyl, butyl,pentyl, hexyl, octyl, decyl, dodecyl, and octadecyl, and thecorresponding branched-chain isomers thereof. Lower alkyl groups, of oneto about six carbon atoms, are preferred. The alkyl groups optionallysubstituted by hydroxy groups include alkyl groups as hereinbeforedefined substituted with a hydroxy group at any position, such as butnot limited to the following examples: hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,6-hydroxyhexyl, and the like. Hydroxy-substituted lower alkyl groups asdefined above are preferred. Similarly, the alkoxy groups contain fromone to about eighteen carbon atoms, and include, for example, methoxy,ethoxy, propoxy, butoxy, pentoxy, hexoxy, decoxy, and octadecoxy, andthe corresponding branched-chain isomers thereof. Lower alkoxy groups ofone to about 6 carbons, are preferred. The alkoxycarbonylalkyl groupsencompassed by the above formula include those wherein the alkoxyportion contain from one to about eighteen carbon atoms and the alkylportion contains from 1 to about eighteen carbon atoms. Typicalalkoxycarbonyl portions are those such as acetoxy or ethanoyloxy,propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, decanoyloxy, andoctadecanoyloxy, and the corresponding branched chain isomers thereof.

[0146] The aryl groups encompassed by the above formula are thosecontaining 6-10 carbon atoms, such as naphthyl, phenyl and alkyl oralkoxy substituted-phenyl, e.g., toluyl and xylyl.

[0147] For the purposes of this invention, the compounds of the presentinvention are formed as biologically and pharmaceutically acceptablesalts. Useful salt forms are the halides, particularly the bromide andchloride, tosylate, methanesulfonate, and mesitylenesulfonate salts.Other related salts can be formed using similarly non-toxic, andbiologically and pharmaceutically acceptable anions. As described in theformula above, the heterocyclic group may be represented by the R groupof the formula —CH₂C(═O)—R, or it may represent the R′ group of theformula —CH₂C(═O)—NHR′.

[0148] Representative, non-limiting examples of compounds of the presentinvention are:

[0149] 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]thiazolium bromide;

[0150] 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4,5-dimethylthiazoliumbromide;

[0151]3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide;

[0152]3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dimethylthiazoliumchloride;

[0153]3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(6-hydroxyethyl)thiazoliumbromide;

[0154]3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dimethylthiazoliumbromide;

[0155] 3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide;

[0156] 3-(2-(2-furanyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide;

[0157] 3-(2-(2-furanyl)-2-oxoethyl)-4-(2-hydroxypentyl)thiazoliumbromide;

[0158] 3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dimethylthiazoliumbromide;

[0159] 3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-dimethyl-thiazoliumbromide;

[0160]3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dimethylthiazoliumbromide;

[0161] 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazoliumbromide;

[0162] 3-(2-(2-thienyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide;

[0163] 3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-hydroxyethylthiazoliumbromide 3-(2-(4-thiomorpholinyl)-2-oxoethyl)-4,5-dimethylthiazoliumbromide;

[0164] 3-(2-(hexahydro-1 -azepinyl)-2-oxoethyl)-4,5-dimethylthiazoliumbromide;

[0165]3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazoliumchloride;

[0166] 3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-dimethyl-thiazoliumbromide 3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide;

[0167] 3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazoliumchloride;

[0168]3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazoliumchloride;

[0169] 3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazoliumchloride;

[0170] 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazoliumchloride;

[0171] 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-octylthiazoliumbromide;

[0172] 3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide;

[0173]3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dipropylthiazoliumchloride;

[0174] 3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-di(octadecyl)thiazoliumbromide;

[0175]3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dipentylthiazoliumbromide;

[0176] 3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-didodecylthiazolium bromide;

[0177] 3-(2-(2-furanyl)-2-oxoethyl)-5-decylthiazolium bromide;

[0178]3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dioctylthiazoliumbromide;

[0179] 3-(2-(1-pyrrolidiny)-2-oxoethyl)-4,5-diethylthiazolium bromide;

[0180]3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dipentylthiazoliumbromide;

[0181] 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]-thiazolium bromide;

[0182] 3-(2-(2-thienyl)-2-oxoethyl)-thiazolium bromide ;

[0183]3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-(6-hydroxyhexyl)thiazoliumbromide;

[0184] 3-(2-(4-thiomorpholinyl)-2-oxoethyl)thiazolium bromide;

[0185] 3-(2-(hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dioctylthiazoliumbromide;

[0186] 3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-didecylthiazoliumbromide;

[0187] 3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dioctylthiazolium bromide;

[0188] 3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dipropylthiazoliumchloride;

[0189] 3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4-methylthiazoliumchloride;

[0190] 3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-5-methylthiazoliumchloride;

[0191] 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4-octylthiazoliumchloride;

[0192] The compounds represented by Formula II are disclosed in U.S.Pat. No. 6,121,300. The syntheses of these compounds, discussed in U.S.Pat. No. 6,121,300, are hereby incorporated by reference herein.Pharmaceutical compositions may be prepared with a therapeuticallyeffective quantity of the agents or compounds of the present inventionand may include a pharmaceutically acceptable carrier, selected fromknown materials utilized for this purpose. Such compositions may beprepared in a variety of forms, depending on the method ofadministration. Also, various pharmaceutically acceptable addition saltsof the compounds of the present invention may be utilized.

[0193] In a further embodiment, the present invention relates to methodsfor treating hair and nails and ex-vivo treatment of organs, cells andtissues that comprise contacting the targeted area with a composition ofthe present invention. In an embodiment, for topical application to hairor nails, a solution, a lotion or ointment may be formulated one or morewith agents or compounds in a suitable vehicle such as water, ethanol,propylene glycol, perhaps including a carrier to aid in contacting thehair or nails. For example, a topical preparation could include up toabout 10% of the compound of Formula I or II, or mixtures thereof. Othersuitable forms for administration to other body tissues are alsocontemplated.

[0194] The agent or compound of Formula I or II is formulated incompositions in an amount effective to return the biomechanical anddiffusional characteristics of the sample to the state of a healthy 20year old. This amount will, of course, vary with the particular agentbeing utilized and the particular dosage form, but typically is in therange of 0.01% to 1.0%, by weight, of the particular formulation.

[0195] In one embodiment relating to the treatment of hair, thecompounds discussed above may be combined with other components to forma composition that may be used to treat: (a) damaged hair; (b)physiologically aged hair; and (c) diseased hair (e.g. diabetes). Thecompositions of the present invention may be compounded and/or mixedwith shampoo compositions containing, anionic, nonionic and cationicsurfactants, as well as hair conditioning compositions. In yet anotherembodiment, the compositions of the present invention may beincorporated with conventional hair treating compositions such asbleaching compositions, hair dyeing compositions and/or hair relaxers.

[0196] In an embodiment that includes a hair treatment composition ofthe present invention, surface active agents may be used and include,but are not limited to, coconut oil fatty acids or oleic acid, alkalimetal or ammonium or amine soaps, water-soluble lauryl sulfate salts,usually alkali metal, ammonium and ethanolamine, commonly diethanolamineor triethanolamine, salts; alkanolamine salts of linear C₁₂-C₁₅ alkylbenzene sulfonic acids; water-soluble polyethoxylauryl alcohol sulfatesalts; linear alkyl benzene polyoxyethyl sulfonate salts; sulfatedlauric acid monoglyceride salts; quaternary ammonium compounds such ascetyltrimethyl ammonium chloride; nonionic detergents such asoctylphenoxypoly(ethyleneoxy)ethanol; and amphoteric detergents.

[0197] In a further embodiment, a shampoo composition of the presentinvention may include foam boosters or foam stabilizers. Such boostersinclude, but are not limited to, dialkylolamides of C₈-C₁₈ fatty acids,as, for instance, lauric or cocodiethanolamides which are represented bythe formula R—CO—N—(CH₂—CH₂—OH)₂ where R—CO is a saturated fatty acidacyl radical of C₈-C₁₅ fatty acids, particularly lauric acid or myristicacid or mixtures of saturated fatty acids containing predominately fromC₁₂ to C₁₄ fatty acids and commonly derived from coconut oil.

[0198] In one embodiment, the composition for treating hair may beadjusted to a pH from about 6 to about 9, more particularly from about5.5 to about 7.5.

[0199] In a further embodiment, the composition for treating hair mayinclude supplemental ingredients for particular purposes such aspolymers, combing aids, etc.—liquids, gels, creams or dry powders.

[0200] In an embodiment relating to the treatment of nails, thecompounds discussed above may be combined with conventional nail polishcomponents to form a composition that may be used to treat: (a) damagednails; (b) physiologically aged nails; and (c) diseased nails (e.g.diabetes). The nail polish compositions of the present invention mayinclude various solvents, resins, FDA certified pigments, and pigmentextenders. The following are illustrative examples of each of thesecomponents. For example, solvents may include n-butyl acetate (estersolvent), ethyl acetate (ester solvent), propylene glycol methyl etheracetate (ester solvent), isopropyl alcohol (oxygenated solvent),dipropylene glycol methyl ether (glycol ether solvent),naphtha/petroleum naphtha (aliphatic petroleum solvent) mineral spirits(aliphatic petroleum solvent). For example, resins may include acrylicresin (a polymer of acrylic-methacrylic acids and their esters),maleated-rosin (rosin-maleic adduct), nitrocellulose (soluble celluloseester), pigment. In addition, FD&C colors and/or FDA certified pigmentsmay be used. In a further embodiment, pigment extenders may be used suchas magnesium silicate (Vantac 6H), silicone dioxide (amorphous silica),aluminum stearate, calcium carbonate, barium sulfate, aluminum silicate,calcium silicate and calcium sulfate.

[0201] In a further embodiment, the composition of the present inventionmay include antifungal agents such as miconazole nitrate, ketoconazole,itraconazole, fluconazole, econazole, terconazole, saperconazole,amorolfine, ciclopirox, oxiconazole, clotrimazole, terbinafine,naftifine, and other antifungal drugs that are available in a topicalformulation. In addition, the formulation containing the antifungal drugmay include an agent such as hydroxypropyl-alpha -cyclodextrin thatenhances the water-solubility of the antifungal drug. The anti-fungaldrugs are used in anti-fungally effective amounts. For example,anti-fungally effective amounts may be from about 0.5% to about 10%, byweight, and more particularly from about 1% to about 5%, by weight, ofthe formulation that is applied to the nail or surrounding dermaltissue.

[0202] In another embodiment, the present compositions may be applied inthe area of tissue “rejuvenation”. For purposes of the presentinvention, the terms “cells”, “tissues” and “organs” may be usedinterchangeably as organs consist of tissue and tissue contain cells andextracellular material. The term “rejuvenation” means sufficientlyimproving the deformability and/or diffusion coefficient of cells,tissues and/or organs from a state of decreased deformability andimpaired diffusional characteristics, as typically observed in cells,tissues or organs of older individuals, to a state of increaseddeformability and improved diffusional characteristics, as commonly seenin cells, tissues and organs of healthy and young individuals (e.g., 20years old). One method of determining whether the cells, tissues ororgans have been “rejuvenated” is whether, after treatment with thecompositions of the present invention, the biomechanical and diffusionalcharacteristics of the treated cells, tissues or organs have beenchanged by at least 20% toward the characteristics of a healthy 20 yearold.

[0203] Decreased deformability is associated with impaired tissue ororgan functionality in itself, as optimal biomechanical function isdemonstrated at deformability levels measured in healthy and youngindividuals and diminishes with progressively decreasing levels ofdeformability. It is believed that the aging process, in addition tomodifying the deformability, also induces additional specificimpairments in the functionality of cells, tissues and/or organs thatare not directly related to deformability. It is further believed thatthis impairment in functionality is related to an altered diffusioncoefficient of molecules across intracellular and extracellular spaces.The decreased ability of molecules to traverse intra- and extracellularspaces may affect signaling functions of hormones and cytokines,transportation of oxygen and nutrients from the vascular space to thecell, and cellular metabolism.

[0204] Table 1 below is an illustrative list of various types oftissues, cells and organs that may be treated with the composition andmethod of the present invention. This list is merely illustrative andshould not be construed as limiting the invention. TABLE 1 Cells TissuesOrgans Beta cells of pancreas Tendons Heart Cardiac myocytes LigamentsLungs Neurons Bone Kidneys Macrophages Vessels Liver ErythrocytesCardiac valves Spleen Leukocytes Cornea Adrenals Fibrocytes Gonads Skin

[0205] For purposes of the present invention, “rejuvenation” may bemeasured by one or more of the techniques to measure deformabilityand/or other functionality of tissues, cells or organs. Commonly usedmethods to determine deformability include ultrasonographic techniquesand the determination of volume-pressure and stress-strainrelationships, but are not limited to these. Table 2 is an illustrativelist of some of the currently available measures used for evaluatingaspects of deformability: This list is merely illustrative and shouldnot be construed as limiting the techniques that may be used to measurethe deformability of tissues, cells or organs. TABLE 2 Cells TissuesOrgans In vitro Membrane Compliance Compliance deformabilityDistensibility Distensibility Impedance Impedance Tensile strength Walltension Wall tension Compressive strength Compressive strengthFlexibility Flexibility Torsion Torsion Elasticity ElasticityViscoelasticity Viscoelasticity Shear Shear In vivo Membrane ComplianceCompliance deformability Distensibility Distensibility ImpedanceImpedance Wall tension Wall tension Flexibility Flexibility ElasticityElasticity Viscoelasticity Viscoelasticity

[0206] Another method of determining the degree of “rejuvenation” forthe present invention is to measure the diffusion coefficient ofmolecules across intracellular and extracellular spaces. Methods used tomeasure the diffusion coefficient of molecules across intracellular andextracellular spaces include the determination of the reaction time ofbiomolecular feed-back mechanisms based on the diffusion of moleculesacross a cellular, tissue and/or organ space to reach a target responseelement and the measurement of the diffusion rate of certain moleculesacross biological spaces or the diffusion rate of tracer molecules likedyes or radioisotopes. Examples of methods to determine the biomolecularfeed-back mechanisms include, but are not limited to, the following: (a)hypothalamic-pituitary axis: growth hormone, ACTH, TSH, or prolactin;(b) pituitary-adrenal axis: cortisol; (c) pituitary-thyroid axis:thyroxin; and (d) pituitary-gonadal axis: sex hormones, LH, and FSH.Examples of methods to determine the diffusion rate of certain moleculesacross biological spaces include, but are not limited to, the following:arterio-alveolar oxygen and carbon dioxide gradients; insulinresistance; and arterio-venous oxygen gradient (e.g., heart, muscle).

[0207] In one embodiment, the compounds of the present invention may becombined with a pharmacologically acceptable organ storage solution thatresults in a rejuvenation solution. The solution of the presentinvention may be utilized to rejuvenate major organs such as the kidney,heart, pancreas, liver, lungs and intestines and portions or segmentsthereof. In another embodiment, organs may be rejuvenated by flushingthe organ after it has been removed from a cadaver with the rejuvenationsolution of the present invention followed by cold storage of the organin the rejuvenation solution at temperatures of about 4° C. Organsstored in the rejuvenation solution may then be transplanted into anappropriate transplant recipient.

[0208] For example, the rejuvenation solution of the present inventionmay be a pharmacologically acceptable solution such as an aqueous buffersolution containing one or more of the specific compounds claimed. Inone embodiment, an aqueous phosphate buffer may be prepared, forexample, by mixing sodium hydrogen phosphate (Na₂HPO₄) and sodiumdihydrogen phosphate (NaH₂PO₄) in water preferably; the water should bepurified by distillation, deionization, etc. prior to use. In a furtherexample, if a cardioplegic solution for rejuvenation of hearts isdesired, a phosphate buffer solution may be prepared using potassiumhydrogen phosphate (K₂HPO₄) and/or potassium dihydrogen phosphate(KH₂PO₄).

[0209] In a further embodiment, the rejuvenation composition of thepresent invention may be adjusted to have a pH of 7.0 or greater; moreparticularly in the range of 7.1-7.4.

[0210] In another embodiment, the rejuvenating solutions of the presentinvention may contain an osmotic agent. Suitable conventional osmoticagents include any osmotic agent known for use in preservationsolutions, including mannitol, sucrose, raffinose, and lactobionate. Theosmotic agent is added to the rejuvenating solution in a sufficientamount to provide adequate osmolality and rejuvenation properties.

[0211] In yet another embodiment, the rejuvenating solution of thepresent invention may contain other components which do not adverselyaffect the rejuvenating properties of the solution. For example,addition of glutathione or a C₁₋₆ alkyl glutathione monoester (M. E.Anderson et al, Arch. Biochem. Biophys., 1985, 239:538-548, ethyl ester)in amounts of about 2-10 mmol/l.

[0212] In a further embodiment, a suitable hypothermic solution, such asthe solution formulated by the University of Wisconsin, that may becombined with the compositions of the present invention to rejuvenatethe kidney, is composed of Sodium (30 mmol L⁻¹), Potassium (125 mmolL⁻¹), Magnesium (5 mmol L⁻¹), Sulphate (5 mmol L⁻¹), Lactobionate (100mmol L⁻¹), Phosphate (25 mmol L⁻¹), Raffinose (30 mmol L⁻¹), Adenosine(5 mmol L⁻¹), Gluthatione (3 mmol L⁻¹), Allopurinol (1 mmol L⁻¹),Insulin (100 units L⁻¹), Dexamethasone (8 mg L⁻¹), Bactrim (0.5 ml), HES(50 g L⁻¹), Osmolality (320 mmol kg⁻¹), and pH of 7.4.

[0213] Further embodiments of suitable cold storage solutions that maybe combined with the compositions of the present invention to rejuvenatethe kidney comprise the Collins solution (Collins, B M, Lancet1969;2:1219) and the Euro-Collins solution (Squifflet J P, TransplantProc 1981;13:693). Examples of further embodiments of suitablepreservation solutions that may be combined with the compositions of thepresent invention to rejuvenate the heart comprise the aforementionedUniversity of Wisconsin solution, the Stanford solution (Stein D G, JThorac Cardiovasc Surg 1991;102:657) and the St. Thomas' solution(Demertzis S, Ann Thorac Surg 1993;55:1131).

[0214] Examples of further embodiments of suitable pneumoplegiasolutions that may be combined with the compositions of the presentinvention to rejuvenate the lung comprise the Euro-Collins and theUniversity of Wisconsin solutions.

[0215] In a further embodiment, a suitable preservation solution thatmay be combined with the compositions of the present invention torejuvenate a liver is the Euro-Collins solution. In yet a furtherembodiment, a suitable preservation solution that may be combined withthe compositions of the present invention to rejuvenate a liver consistsof the University of Wisconsin solution. Examples of further embodimentsof suitable preservation solutions that may be combined with thecompositions of the present invention to rejuvenate the small bowelscomprise the Euro-Collins and the University of Wisconsin solutions.

[0216] Methodology for Determination of Stress vs Strain Relationship

[0217] (Stiffness)

[0218] The distensibility (i.e, elasticity, rigidity, shear, tensilestrength, compression, etc.) of hair, nails, tendons, etc. may bedetermined using widely available commercial devices, such asmanufactured by Instron. Alternatively, other test methods known to apractitioner of the art may be employed.

[0219] The test assay for determining whether hair has been“rejuvenated” for the present invention is the following. Individualscalp hairs were cemented into the ends of glass capillary tubes suchthat several centimeters of the shaft protruded from the end. This hairwas then trimmed to extend 18 mm from the end of the tube. The unit wasthen inserted into a micropipette positioner for study. Evaluationconsisted of bending the hair by applying a specified force anddisplacement. Thus, this determination of stress vs strain of bendingassessed elasticity, compressibility, and shear of each hair shaft. Eachhair served as its own control, with baseline and post-treatmentproperties assessed and directly compared.

[0220] A 1 mm thick plate with a 0.5 mm diameter hole drilled throughwas attached to the surface of an isometric strain gauge. To performeach measurement, the capillary tube was placed over the fenestratedplate and the hair end inserted into the hole in the plate withouttouching the strain gauge. The hair was then straightened, if necessary,such that its axis formed a 10 degree angle with respect to vertical.Once positioned, the hair was then lowered onto the surface of thestrain gauge. The force required to bend each hair a specified distancewas determined over a wide range of displacements. From the stress vsstrain relationships thus derived, the work to bend each hair underdifferent treatment regimens can be directly compared. For purposes ofthe present invention, the term “rejuvenated” hair means an improvementof at least 20% in the measured value of the treated hair, toward thevalues seen in young, undamaged hair (i.e. healthy 20 year old).

[0221] To determine changes in deformability of nails treated with arejuvenator, a nail specimen is trimmed to standard dimensions(thickness and cross sectional area) and dried for 2 hours in an oven at45° C. The nail is then clamped within an Instron materials testingdevice. A stress vs strain relationship is determined using thisinstrument, taking care to perform testing only within the region ofreversibility (i.e., not to apply excessive stress). The nail specimenis then removed from the materials testing device and exposed to atissue rejuvenator bath at a concentration and for a time needed toprovide the desired change in deformability. The nail specimen is thenwashed in distilled water twice for 10 minutes each and dried in an ovenat 45° C. for 2 hrs. A new stress vs strain relationship is thenobtained after this treatment. This shows that the strain for a specificstress is reduced by about 50%. For purposes of the present invention,the term “rejuvenated” nail means an improvement of at least 20% in themeasured value of the treated nail, toward the values seen in young,undamaged nails (i.e. healthy 20 year old).

[0222] The following examples will more fully illustrate the embodimentsof this invention. Therefore, they should not be construed as limitingof the remainder of the disclosure in any way. All parts, percentage andproportions referred to herein and in the appended claims are by weightunless otherwise indicated.

EXAMPLE 1 Effect of Rejuvenator on Hair Deformability

[0223] Individual hairs were prepared within capillary tubes asdescribed above. The stress versus strain relationship was determined asa baseline. Subsequently, the hair was immersed in a solution of3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride (1 mM) for 15minutes. The hair was then removed from the bath and rinsed for 5minutes in distilled water and dried. The results are shown in FIG. 1,which illustrate that after treatment with a rejuvenator, the hairpossessed increased distensibility, as indicated by the fact that forstress greater than 0.08, the resulting strain is about 50% less thanthat before treatment.

EXAMPLE 2 Rejuvenator Shampoo Composition

[0224] The following shampoo composition is prepared employing acompound of the present invention and is applied to hair. ComponentWeight (%) Sodium Lauryl Sulfate (30%) 40.00 Laurie Diethanolamide 4.003-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium 1.10 chloride Perfume0.25 Dowicil 200 0.20 Soft Water 54.45

EXAMPLE 3 Rejuvenator Nail Polish Composition

[0225] The following nail polish composition is manufactured accordingto conventional methods containing the compounds of the presentinvention. Amount Weight (%) Nitrocellulose (¼″ RS) 15.00 Nitrocellulose(½″ RS) 5.00 Dipropylene Glycol Di-P-Aminobenzoate 10.00 NeopentylGlycol Dioctanoate 5.00 Toluene 47.80 Ethyl Acetate 10.00N-Methyl-2-Pyrrolidone 2.00 Isopropanol 0.503-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium 2.00 chlorideStearalkonium Hectorite 1.00 Titanium Dioxide 0.30 Black Iron Oxide 0.30D&C Red #7 Ca Lake 0.30 D&C Red #34 Ca Lake 0.30 D&C Yellow #5 Zr Lake0.50

EXAMPLE 4 Rejuvenator Nail Composition with Antifungal

[0226] The components outlined below are mixed into a homogeneoussolution which is useful for applying to finger and toe nails forrejuvenation. Component Weight (%) Alcohol SDA 67.0 Miconazole 20.03-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride 2.0 Glycerin 1.0Water 4.0 Propylene glycol 5.0 Hydroxypropyl cellulose 1.0

EXAMPLE 5 Rejuvenator Hair Conditioning Composition

[0227] Ingredient Weight (%) Deionized Water 93.10 Hydroxyethylcellulose1.35 Silicone Copolymer (SF 1188 (GE)) 0.75 Oleyl Alcohol 0.75 DTAC(Lauryl Trimethyl Ammonium Chloride) 2.253-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride 1.0 Germaben II(preservative) 0.50 Perfume 0.30

EXAMPLE 6 Tendon Rejuvenation

[0228] The elasticity of the Achilles tendon of a one year old hen wasdetermined in a materials testing device before and after ex vivoexposure to 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride (1mM) in a bath for 15 minutes. The results are shown in FIG. 2.Post-treatment, distensibility was significantly increased towards thatof a younger chicken. Specifically, for stress greater than 0.04, thetreated tendon exhibits about 50% of the strain of the untreated tendon.

EXAMPLE 7 Tissue Diffusion Coefficient Rejuvenation

[0229] The following is an illustration of a methodology that can beused to rejuvenate ex vivo and prior to transplantation to a recipientpatient the lungs removed from a donor cadaver aged 21 years or more.Older subjects exhibit a decrease in the deformability of pulmonarytissue and in the capacity of gases, including oxygen, to diffuse acrossalveolar membranes. Individuals' deformability and diffusioncharacteristics can be characterized by using the standard methodologyof determination of the lung diffusing capacity for carbon monoxide(e.g., Chang et al., Chest (1992) 102:139-42). The diffusing capacity ismeasured in the supine patient using a single breath of carbon monoxide(0.3%) held for ten seconds using a CPI 5000 IV (Gould Instruments,Houston, Tex.), corrected for alveolar volume. A young subject (20 yearsold) will have approximately a 40% higher diffusion coefficient forcarbon monoxide compared to older subjects (60 yrs). The ex vivo organis flushed once with a cooled preservation solution containing3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride at aconcentration of 0.01 to 1.0 mM. Testing in the recipient patient,following transplantation of the lungs, would show that bothdeformability and diffusional capacity had improved to a statecomparable to the one observed in the lungs of a healthy and youngindividual (i.e., 20 years).

EXAMPLE 8 Rejuvenation of Organs Composition

[0230] A 70 year old male individual and established organ donor isdeclared brain dead 24 hours following a motor vehicle accident duringwhich he sustained serious brain trauma. This individual has no knownhistory of cardiovascular or pulmonary disease, infection with thehepatitis viruses, HIV or neoplastic processes. His organs areconsidered for donation. However, because of his age, donation of thekidneys, heart and lungs would generally not be indicated. Thecomposition and method of the present invention are employed torejuvenate the aged organs to a state compatible with the organs of ayoung individual, exhibiting deformability and diffusion characteristicsof young organs. The regimen applied consists of the ex vivo perfusionof the extracted organs with an accepted preservation solutioncontaining a sufficient concentration of the composition of the presentinvention for a sufficient duration of time, e.g., 15 minutes, followingconventionally established guidelines for the preservation of cells,tissues and/or organs ex vivo. Thereafter, depending on need, the organsare continually perfused with a conventional preservation solution whichmay or may not contain additional concentrations of the compositions ofthe present invention.

[0231] The organ extraction as well as the ex vivo handling andimplantation of the organ into the recipient are in accordance withestablished algorithms and procedures. Prior to implantation, the organmay be flushed with a conventional preservation solution. This flushingprocedure permits the transplantation of an organ free of thecompositions of the present invention.

[0232] It is believed that the transplanted organs, treated as describedherein, would demonstrate improved functionality, both from abiomechanical and molecular diffusion/transportation perspective.Moreover, the tissue rejuvenation technology would also increase thenumber of transplantable organs significantly. There is a great demandfor transplantable organs which is widely exceeding the available supplyof transplantable organs. Alternatively, the technology would alsoimprove the functionality of currently transplantable organs and improvesurvival and clinical outcome of such organs post transplantation.

1. A composition for the treatment of hair, nail, ex-vivo organ, ex-vivocell or ex-vivo tissue to improve the biomechanical and diffusionalcharacteristics comprising an effective amount of a compound selectedfrom the group consisting of compounds of the formula (I):

wherein R¹ and R² are independently selected from the group consistingof hydrogen, hydroxy(lower alkyl), lower acyloxy(lower alkyl), loweralkyl, lower alkenyl, or R¹ and R² together with their ring carbons maybe an aromatic fused ring, optionally substituted by one or more amino,halo or alkylenedioxy groups; Z is hydrogen or an amino group; Y isamino, or a group of the formula —CH₂C(═O)—R wherein R is a lower alkyl,alkoxy, hydroxy, amino or aryl group; said aryl group optionallysubstituted by one or more lower alkyl, lower alkoxy, halo,dialkylamino, hydroxy, nitro or alkylenedioxy groups, or a group of theformula —CH₂ R′ wherein R′ is hydrogen, or a lower alkyl, lower alkynyl,or aryl group, or a group of the formula —CH₂C(═O)—N(R″)R′″ wherein (a)R″ is hydrogen and R′″ is a lower alkyl group optionally substituted bya C₆-C₁₀ aryl group, or a C₆-C₁₀ aryl group, said aryl groups optionallysubstituted by one or more lower alkyl, halo, or (lower alkoxy)carbonylgroups; or (b) R′ and R′″ are both lower alkyl groups; and X is ahalide, tosylate, methanesulfonate, mesitylenesulfonate, or otherpharmacologically acceptable anion and mixtures thereof, and a carriertherefor.
 2. The composition of claim 1 wherein the effective amount issufficient to return the biomechanical and diffusional characteristicsof the hair, nail, ex-vivo organ, ex-vivo cell or ex-vivo tissue to thestate of a healthy 20 year old.
 3. The composition of claim 1 whereinthe effective amount is sufficient to treat at least one of thefollowing: (a) damaged hair; (b) physiologically aged hair; or (c)diseased hair (e.g. diabetes).
 4. The composition of claim 3 wherein thecomposition is in the form of a shampoo composition.
 5. The compositionof claim 1 wherein the effective amount is sufficient to treat at leastone of the following: (a) damaged nails; (b) physiologically aged nails;and (c) diseased nails (e.g. diabetes).
 6. The composition of claim 5wherein the composition is in the form of a nail polish.
 7. Thecomposition of claim 1 wherein the effective amount is sufficient forrejuvenation of the ex-vivo organ, ex-vivo cell or ex-vivo tissue. 8.The composition of claim 7 wherein the composition is combined with apharmacologically acceptable organ storage solution.
 9. The compositionof claim 8 wherein the effective amount is sufficient for rejuvenationof at least one of the following: ex-vivo kidney, ex-vivo heart, ex-vivopancreas, ex-vivo liver, ex-vivo lung and ex-vivo intestine and portionsor segments thereof.
 10. The composition of claim 2 wherein theeffective amount is sufficient to treat at least one of the following:(a) damaged hair; (b) physiologically aged hair; or (c) diseased hair(e.g. diabetes).
 11. The composition of claim 10 wherein the compositionis in the form of a shampoo composition.
 12. The composition of claim 2wherein the effective amount is sufficient to treat at least one of thefollowing: (a) damaged nails; (b) physiologically aged nails; and (c)diseased nails (e.g. diabetes).
 13. The composition of claim 12 whereinthe composition is in the form of a nail polish.
 14. The composition ofclaim 10 wherein the effective amount is sufficient for rejuvenation ofthe ex-vivo organ, ex-vivo cell or ex-vivo tissue.
 15. The compositionof claim 14 wherein the composition is combined with a pharmacologicallyacceptable organ storage solution.
 16. The composition of claim 15wherein the effective amount is sufficient for rejuvenation of at leastone of the following: ex-vivo kidney, ex-vivo heart, ex-vivo pancreas,ex-vivo liver, ex-vivo lung and ex-vivo intestine and portions orsegments thereof.
 17. A composition for the treatment of hair, nail,ex-vivo organ, ex-vivo cell or ex-vivo tissue to improve thebiomechanical and diffusional characteristics comprising an effectiveamount of a compound selected from the group consisting of compounds ofthe formula (II):

wherein R¹ and R² are independently selected from the group consistingof hydrogen and an alkyl group optionally substituted by a hydroxygroup; Y is a group of the formula —CH₂C(═O)R wherein R is aheterocyclic group containing 4-10 ring members and 1-3 heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur; saidheterocyclic group optionally substituted by one or more substituentsselected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl,aryl, and aralkyl groups; and said one or more substituents optionallysubstituted by one or more alkyl or alkoxy groups; or a group of theformula —CH₂C(═O)—NHR′ wherein R′ is a heterocyclic group containing4-10 ring members and 1-3 heteroatoms selected from the group consistingof oxygen, nitrogen, and sulfur; said heterocyclic group optionallysubstituted by one or more alkoxycarbonylalkyl groups; and X is ahalide, tosylate, methanesulfonate or mesitylenesulfonate ion or otherpharmacologically acceptable anion.
 18. The composition of claim 17wherein the effective amount is sufficient to return the biomechanicaland diffusional characteristics of the hair, nail, ex-vivo organ,ex-vivo cell or ex-vivo tissue to the state of a healthy 20 year old.19. The composition of claim 17 wherein the effective amount issufficient to treat at least one of the following: (a) damaged hair; (b)physiologically aged hair; or (c) diseased hair (e.g. diabetes).
 20. Thecomposition of claim 19 wherein the composition is in the form of ashampoo composition.